The present invention relates to a process for the purification of 7-[2-[aminothiazol-4-yl)-2-[(carboxymethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. cefixime of formula 
Cefixime, e.g. in the form of a trihydrate, is a cephalosporin antibiotic with excellent antibacterial properties and high xcex2-lactamase stability (see for example H. Yamanaka et al., J.Antibiotics (1985), 38(12), p 1738-1751).
Cefixim may be prepared via a 7-{2-[(2-aminothiazol)-4-yl]-2-[((aryl-or alk)-oxy-carbonyl)-methoxyimino]acetamido}-3-vinyl-ceph-3-em-4-carboxylic acid, which may be prepared according to a novel process.
In one aspect the present invention provides a process for the production of a compound of formula 
wherein R denotes alkyl or aryl and wherein the amine group attached to the thiazolyl ring is free or protected, comprising reacting a compound of formula 
in free form, protected form or in the form of a salt, with a compound of formula 
wherein R denotes alkyl or aryl and wherein the amine group attached to the thiazolyl ring is free or protected, and isolating a compound of formula V from the reaction mixture, e.g. optionally after splitting off protecting groups and/or converting a compound of formula V in the form of a salt into a compound of formula V in free form.
In formula IV and V R denotes alkyl, e.g. (C1-8)alkyl, such as (C1-4)alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; e.g. methyl; or aryl, e.g. phenyl, preferably alkyl. Alkyl and aryl may be unsubstituted or substituted, e.g. by groups which are inert under appropriate reaction conditions for the acylation of an amine group.
A compound of formula IV wherein R is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl and wherein the amine group is free or protected is novel.
In another aspect the present invention provides a compound of formula IV wherein R is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl and wherein the amine group attached to the thiazolyl ring is free or protected.
A process according to the present invention may be carried out as follows:
A compound of formula IV may e.g. be prepared by reaction of 2-(2-amino-4-thiazolyl)-(Z)-2-((aryl-or alk)-oxycarbonylmethoxyimino))acetic acid with 2,2xe2x80x2-benzothiazolyl disulphide in an organic solvent, e.g. dichloromethane in the presence of a phosphine, e.g. triphenylphosphine or a phosphite, e.g. triethyl phosphite, e.g. at room temperature. Protection groups of the amine group attached to the thiazolyl ring include protection groups which are conventional in xcex2-lactam chemistry, e.g. protection groups as described below for the amine group attached in position 7 of the ring structure of a compound of formula III. Protection of the amine group may e.g. be carried out as conventional.
A compound of formula IV, e.g. produced as described above, e.g. without isolation from the reaction mixture, may be reacted with a compound of formula III. A compound of formula III may be in free form, in the form of a salt, e.g. in alkali salt form or in the form of a salt with ammonia, amines, such as a tertiary amines, e.g. trialkylamines, e.g. wherein the alkyl groups independently of each other each denote e.g. (C1-8)alkyl, such as (C1-4)alkyl e.g. triethylamine or tributylamine; amidines, e.g. DBN or DBU, or guanidines, e.g. tetramethyl guanidine, preferably triethylamine; or a compound of formula III may be in protected form, e.g. wherein functional groups such as the amine group in position 7 and/or the carboxyl group in position 4 of the ring structure are N- and/or O-protected with protecting groups, e.g. as conventional in xcex2-lactam chemistry, such as silyl groups, e.g. trialkylsilyl-, aryldialkylsilyl-, diarylalkylsilyl groups, e.g. in N,O-bissilylated form. The alkyl and aryl groups may be the same or different. Alkyl includes (C1-4)alkyl, aryl includes (C5-18)aryl, e.g. (C6-12)aryl, such as phenyl groups. Preferred protecting groups are trialkylsilyl groups, e.g. trimethylsilyl groups.
A compound of formula III may preferably be in protected from or in the form of a salt, e.g. in the form of a salt.
A compound of formula III in the form of a salt may be prepared e.g. as convenional in xcex2-lactam chemistry, e.g. by addition to a salt forming agent to a mixture of a compound of formula III in organic solvent, or, in situ in a mixture of a compound of formula IV and a compound of formula III, e.g. by addition of a salt forming agent, e.g. an amine or ammonia, to a mixture of a compound of formula III, a compound of formula IV and organic solvent. A compound of formula III in protected form, e.g. N,O-bissilylated, may be prepared e.g. as conventional, e.g. analogously to a method as conventional in xcex2-lactam chemistry. The reaction of a compound of formula III with a compound of formula IV may be carried out in inert organic solvent. Inert organic solvent includes halogenated hydrocarbons, e.g. dichloromethane, carboxylic acid esters, e.g. ethyl acetate, butyl acetate or ketones, e.g. methyl isobutyl ketone, preferably halogentad hydrocarbons; and mixtures of individual inert organic solvent, e.g. as cited above; optionally in the presence of cosolvent, such as an alcohol, e.g. ethanol or methanol, water, or an amide, e.g. dimethylformamide, or a mixture of individual cosolvents, e.g. as cited above. Appropriate reaction temperatures include xe2x88x9240xc2x0 to 60xc2x0 C., such as xe2x88x9215xc2x0 C. to room temperature, e.g. room temperature. Per equivalent of a compound of formula III, 1 to 1.5 equivalents of a compound of formula IV may conveniently be used. A compound of formula V obtained may be isolated and protecting groups optionally present may be splitt off, e.g. analogously to a method as conventional in xcex2-lactam chemistry and/or a compound of formula V in the form of a salt may be converted into a compound of formula V in free form, e.g. according to a method as conventional. A compound of formula V may be obtained in impure form.
A compound of formula V, e.g. in free form or in the form of a hydrate, e.g. in the form of a sesquihydrate, may e.g. also be produced according to a method as conventional, e.g. by acylating a compound of formula III, e.g. in free form, protected form or in the form of a salt, e.g. as described above, with a 4-halo-3-oxo-2-(aryl-or alk)-oxycarbonyl-methoxyimino butyric acid, wherein aryl and alkyl may have the meaning as described above for R in a compound of formula IV or V, and wherein halo denotes halogenide, preferably bromo, chloro, e.g. chloro; e.g. in an activated form, e.g. activated via Vilsmeier formation, or activated in the form of a halogenide, e.g. bromide, chloride, such as chloride, e.g. prepared by reacting 4-halo-3-oxo-2-((aryl-or alk)-oxycarbonyl-methoxyimino butyric acid, with a carboxylic acid halogenide forming agent, e.g. phosphorous oxychloride, e.g. without isolation of 4-halo-3-oxo-2-(aryl-or alk)-oxycarbonyl-methoxyimino butyric acid halogenide from the reaction mixture, to obtain 7-(2-(chloromethylcarbonyl)-2-(Z)((aryl-or alk)-oxycarbonyl)-methoxyimino)-acetamido)-3-vinyl-ceph-3-em-4-carboxylic acid, wherein the carboxylic group in position 4 of the ring system is free, or protected, or in the form of a salt; which is reacted, e.g. without isolation from the reaction mixture obtained, with thiourea to obtain a compound of formula V wherein the carboxylic acid group in position 4 of the ring system is free, or protected, or in the form of a salt and optionally splitting off protecting groups to obtain a compound of formula V and/or converting a salt of a compound of formula V into a free form of a compound of formula V, e.g. according or analogously to a method as conventional. A compound of formula V may be obtained in impure form.
Purification of a compound of formula V is difficult, e.g. because of its poor solubility in common organic solvents, e.g. halogenated hydrocarbons, ketones or esters.
We have now surprisingly found a simple and effective process for the purification of a compound of formula V via formation of a special novel salt.
In another aspect the present invention provides 7-[2-(aminothiazol-4-yl)-2-((aryl-or alk)-oxycarbonylmethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. a compound of formula V, in the form of a salt with tert.octylamine of formula: 
A compound according to the present invention, i.e. (7-[2-(aminothiazol-4-yl)-2-((aryl-or alk)-oxycarbonyl-methoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. a compound of formula V, in the form of a salt with tert.octylamine may be prepared as follows:
A compound of formula V may be reacted with tert.octylamine, e.g. a compound of formula V may be dissolved in the presence of tert.octylamine in organic solvent, for example, alcohols, e.g. methanol, e.g. in a mixture with co-solvents, e.g. in solvent as used in a reaction between a compound of formula III and a compound of formula IV in the presence of alcohol. The amount of the organic solvent, e.g. alcohol, should be sufficient that a solution is obtained. A non-solvent, for example an ester, e.g. ethyl acetate or butyl acetate, a ketone, e.g. methyl isobutyl ketone, or a chlorinated hydrocarbon e.g. dichloromethane, or a mixture of individual solvents, e.g. as mentioned above, may be added to the solution obtained and a compound according to the present invention may crystallise. Crystallisation may be supported by distilling off (parts of) the previously added alcohol. The amount of tert.octylamine is not critical. Preferably between one and two equivalents of tert.octylamine per equivalent of compound of formula V may be used. A compound according to the present invention may be isolated, e.g. according to a method as conventional, e.g. by filtration, centrifugation. A non-solvent is understood to be a solvent (system) in which on addition to a solvent system the solubility of the compound is lowered.
In another aspect the present invention provides a process for the production of a 7-[2-(aminothiazol-4-yl)-2-((aryl-or alk)-oxycarbonylmethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. a compound of formula V, in the form of a salt with tert.octylamine, comprising reacting 7-[2-(aminothiazol-4-yl)-2-((aryl-or alk)-oxycarbonylmethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid with tert.octylamine and isolating a 7-[2-(aminothiazol-4-yl)-2-((aryl-or alk)-oxycarbonylmethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. a compound of formula V, in the form of a salt with tert.octylamine, e.g. in crystalline form.
A compound of formula V in the form of a salt with tert.octylamine may be prepared without isolation of a compound of formula V from its production reaction mixture, e.g. in a one pot reaction.
In the production of a compound of formula V via reaction of a compound of formula III with a compound of formula IV, e.g. as described above, a compound of formula IV may be replaced by an activated ester other than described above, or via an amide of 2-(2-amino-4-thiazolyl)-(Z)-2-((aryl-or alk)-oxycarbonyl)methoxyimino)acetic acid, e.g. of formula 
wherein R1 is xe2x80x94Oxe2x80x94P+(Ph)3Clxe2x88x92, xe2x80x94Oxe2x80x94P(S)(OR4)2, xe2x80x94O-benztriazol-1-yl, xe2x80x94Sxe2x80x94(2-methyl-thiadiazol-5-yl), xe2x80x94Sxe2x80x94Oxe2x80x94CHxe2x95x90N+(CH3)2Cl31  or -benztriazol-1-yl-3-oxide.
Such esters are known and may be preparad as conventional or analogously to a method as conventional.
In another aspect the present invention provides a process for the production of compound of formula V in the form of a salt with tert-octylamine comprising the steps
(i) reacting a compound of formula III in free form, protected form or in the form of a salt with an activated ester of 2-(2-amino-4-thiazolyl)-(Z)-2-((aryl-or alk)-oxycarbonyl)-methoxyimino)acetic acid, e.g. and optionally splitting off protecting groups, and optionally converting a compound of formula V in salt form to obtain a compound of formula V in free form, and
(ii) reacting a compound of formula V in free form obtained in step (i) with tert.-octylamine; e.g. wherein in step (i) an activated ester of 2-(2-amino-4-thiazolyl)-(Z)-2-((aryl-or alk)-oxycarbonyl)-methoxyimino)acetic acid is used without isolation from its production process, e.g. wherein steps (i) and (ii) are carried out in a one-pot reaction.
In another aspect the present invention provides a process for the production of compound of formula V in the form of a salt with tert-octylamine comprising the steps
(i) acylating a compound of formula III, e.g. in free form, protected form or in the form of a salt with a 4-halo-3-oxo-2-(aryl-or alk)-oxycarbonyl-methoxyimino butyric acid, wherein halo denotes halogenide, in an activated form, to obtain a 7-(2-(chloromethylcarbonyl)-2-((Z)((aryl-or alk)-oxycarbonyl)methoxyimino)-acetamido)-3-vinyl-ceph-3-em-4-carboxylic acid, e.g. in free form or in salt form, wherein the carboxylic acid group in position 4 of the ring system is protected or unprotected,
(ii) reacting a 7-(2-(chloromethylcarbonyl)-2-((Z)((aryl-or alk)-oxycarbonyl)methoxyimino)-acetamido)-3-vinyl-ceph-3-em-4-carboxylic acid obtained in step (I) with thiourea, e.g. and optionally splitting off protecting groups to obtain a compound of formula V, e.g. in free form or in salt form, and optionally converting a compound of formula V in the form of a salt to obtain a compound of formula V in free form, and
(iii) reacting a compound of formula V in free form obtained in step (i) with tert.-octylamine; e.g. wherein in step (i) 4-halo-3-oxo-2-(aryl-or alk)-oxycarbonyl-methoxyimino butyric acid in an activated form is used without isolation from its activation process, e.g. wherein steps (i), (ii) and (iii) are carried out in a one-pot reaction.
A compound according to the present invention may be obtained in highly pure form, e.g. higher than 98.9%, e.g. from 98.9 up to 99.5% and more, e.g. 99.3% and more, e.g. directly from a reaction mixture between a compound of formula III and a compound of formula IV or directly from a reaction mixture of 7-(2-(chloromethylcarbonyl)-2-((Z)((aryl-or alk)-oxycarbonyl)methoxyimino)-acetamido)-3-vinyl-ceph-3-em-4-carboxylic with thiourea, e.g. without isolation of a compound of formula V. A compound of formula V may thus be produced in highly pure form and in high yields in a one pot reaction starting from a compound of formula III.
A compound of the invention may be converted into a compound of formula V, e.g. by pH adjustment of a solution thereof, e.g. an aqueous solution, e.g. as conventional, e.g. by addition of an acid, to obtain a compound of formula V in highly pure form (e.g. corresponding to the purity of a compound of the present invention, or even higher). A compound of formula V may be converted into 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. cefixime, e.g. in free form, e.g. in the form of a trihydrate, e.g. as conventional, e.g. by saponification of the ester group attached to the carbonyliminomethoxy group to obtain the free carboxylic acid, e.g. by a method as conventional.
A compound according to the present invention may also directly be converted into 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. cefixime, e.g. in free form, e.g. in the form of a trihydrate, in a one pot reaction by saponification of the ester group attached to the carbonyliminomethoxy group to obtain the free carboxylic acid and pH adjustment of the reaction mixture. Conversion may be carried out as follows:
A compound according to the present invention may be dissolved in water. The pH of the solution obtained may be adjusted to a basic value, e.g. higher than 8, e.g. by addition of a base, e.g. alkali hydoxide, carbonate. Saponification may be terminated within short time. The pH of a solution obtained may be adjusted to around 7, e.g. by addition of an acid, e.g. an organic or inorganic acid, or both. 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)-acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. cefixime, e.g. in free form, e.g. in the form of a trihydrate may crystallise, e.g. upon addition of a non-solvent, e.g. alcohols such as ethanol and may be isolated, e.g. as conventional, e.g. by filtration, centrifugation. Purity of 7-[2-(aminothiazol-4-yl)-2-(carboxymethoxyimino)-acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid thus obtained may be corresponding to that of a compound of the present invention or even higher, e.g. higher than 98.9%, e.g. between 98.9 and 99.5%, e.g. 99.3%.
In another aspect the present invention provides a process for the production of cefixime comprising converting a compound of formula V in the form of a salt with tert.octylamine into 7-[2-(aminothiazol-4-yl)-2-(Z)(carboxymethoxyimino)acetamido]-3-vinyl-3-ceph-3-em-4-carboxylic acid, e.g. a compound of formula II, e.g. cefixime, e.g. in the form of a hydrate, such as a trihydrate, e.g. wherein a compound of formula V is prepared as described herein.
Formation of a compound of the present invention, which may be crystalline, may be highly useful, e.g. it may have a high purification effect on the purity of a compound of formula V. A compound of formula V in the form of a salt with tert.octylamine may surprisingly be prepared in a one pot reaction starting from a compound of formula III, e.g. according to a novel method for the production of a compound of formula V via a novel compound of formula IV or according to a known process for the production of a compound of formula V. A compound of formula V may be converted into cefixime having a purity of up to 99% and more.
In another aspect the present invention provides a tert.-octylamine salt of 7-[2-(aminothiazol-4-yl)-2-((aryl-or alk)-oxycarbonylmethoxyimino)-acet-amido]-3-vinyl-3-ceph-3-em-4-carboxylic acid of formula 
In another aspect the present invention provides the use of a compound of the present invention in the production of cefixime.
The following examples are intended to illustrate the invention without limiting its scope All temperatures are given in degrees Celsius.